Project Summary/Abstract The goal of this R01 proposal is to develop high-performance antimicrobial fluoride-releasing dental materials (composite and dentin bonding agent). Secondary (recurrent) caries and bulk fracture are the leading causes of failure of composite restorations and thus limit their service life. Much effort has been directed towards the development of dental materials that can inhibit bacterial biofilms and reduce secondary caries. However, the composites containing soluble anticariogenic agents or (nano)particles of ACP or CaF2 usually have poor mechanical properties. The antibacterial materials containing silver nanoparticles usually have unacceptable dark shade. In our previous funding period (R01DE019203), we synthesized several novel F-releasing methacrylate monomers and antibacterial monomer containing long-chain quaternary ammonium salts (QAS). We developed a series of novel antibacterial fluoride-releasing materials (dental composites, bonding agents and sealants). They have shown enhanced fluoride-releasing and recharge capabilities, promising antibacterial effect, and good mechanical properties or bonding strength. However, the amount of antibacterial monomers that could be incorporated in these materials was rather limited (~3%) thus limiting its antibacterial activity. To overcome this limitation, we synthesized several new antibacterial monomers bearing different chain lengths and we discovered that a small amount (1-1.5%) of a short-chain QAS monomer, when used together with other long-chain QAS, could significantly increase antibacterial effect. Additionally, it could improve the mechanical properties of the composite. We have also developed new translucent silica-zirconia- yttria ceramic nanofibers and white gallium (hydrous)oxide-loaded mesoporous silica nanopartilces (Ga@MSN). Gallium (III) ions and compounds are safe antimicrobial agents but they have not been used in resin-based dental materials. We hypothesize: (1) the synergistic combination of antibacterial monomers containing varying chain lengths (enhanced contact-killing) and gallium (hydrous)oxide nanoparticles (pH- responsive controlled release of Ga ions) can significantly increase the antibacterial and biofilm-inhibitory effects; and (2) the new antimicrobial fluoride-releasing dental material system will possess significant anti- caries efficacy, excellent mechanical properties, desirable aesthetics, and a long service life. In this proposed project, we will further develop novel high-performance antimicrobial fluoride-releasing dental materials with three aims: In Aim 1, we will formulate and optimize a series of high-performance antimicrobial fluoride- releasing dental materials (composite and dentin bonding agent) by blending the fluoride-releasing monomer and new antibacterial monomers, Ga@MSN, translucent ceramic nanofibers and halloysite nanotubes, fluoride-releasing glass particles, and photoinitiators. We will test and optimize the physical and mechanical properties, bonding strength, cytotoxicity and biocompatibility.. In Aim 2, we will test the hypothesis that the novel antimicrobial F-releasing dental materials will significantly reduce cariogenic bacterial biofilms and secondary caries using an in vitro biofilm-artificial caries model on extracted teeth. In Aim 3, in collaboration with Dr. Hyun Koo at University of Pennsylvania, we will test the hypothesis that the novel antimicrobial F- releasing dental materials will significantly reduce secondary caries using in vivo animal (rat) caries models. Our long-term goal is to develop a new generation of dental materials that have a high efficacy to inhibit oral biofilm formation as well as excellent mechanical properties. The novel dental materials developed in this project will have significantly longer service life and will be excellent candidates for clinical trials of high caries-risk patients.